Classic Neurotransmitters, Neuropeptides, and Atypical Neurotransmitters
Classic Neurotransmitters, Neuropeptides, and Atypical Neurotransmitters
What are they, and what's the difference?
Classic Neurotransmitters
Neurotransmitters are the molecules responsible for chemical transmission between a neuron and its target, a muscle or another neuron. The neurotransmitters we usually think of are the small molecule neurotransmitters like dopamine, serotonin, glutamate, GABA, acetylcholine, etc. Let’s call these the classic neurotransmitters, the most frequently talked about. To be classified as a classic neurotransmitter, they must fit the following criteria:
Synthesized and stored in the presynaptic terminal
Released in response to an action potential in a calcium dependent manner
Has specific postsynaptic receptors
Produces rapid and readily reversible changes in the postsynaptic cell
Mechanism for removal from the synapse
These molecules can be individual amino acids (glutamate, GABA, glycine) or other relatively small molecules synthesized from amino acids or other molecules (i.e dopamine from tyrosine, serotonin from tryptophan). Once synthesized in the terminal, they are stored in small vesicles in the synaptic terminal awaiting release. When the action potential reaches the terminal, calcium ions enter the cell and facilitate their release to go act on postsynaptic receptors.
Neuropeptides
A peptide is a small protein consisting of a few amino acids, so neuropeptides are just small proteins that can act as neurotransmitters. This group includes endogenous opioids, pituitary hormones (i.e. growth hormone-releasing hormone), and many more. Their functions extend beyond those of just a neurotransmitter though, with some being released into the blood as hormones (i.e. oxytocin, vasopressin).
Neuropeptides are synthesized in the cell bodies of neurons, differing from classic neurotransmitters. They are then transported to the terminal where they are stored in large dense-core vesicles, which are located further from the synapse than the small molecule vesicles. Since they are located in the same terminals as small molecule neurotransmitters, it is important to note that they can have longer lasting modulatory effects on the postsynaptic cell that enhance or inhibit classic neurotransmitter signaling. This allows for a lot of flexibility in neurotransmission because neuropeptides require a different stimulus in the terminal to be released, typically a prolonged presence of calcium, as opposed to a short burst for classic neurotransmitters. In this way, different patterns of activity can lead to release of just classic neurotransmitters, just neuropeptides, or both. Neuropeptides also have a longer lifespan than classic neurotransmitters once released, allowing them to diffuse and affect multiple synapses even if only released from one.
Atypical Neurotransmitters
In this category we have purines, endocannabinoids, and gasses. They are atypical because they function in different ways than the classic neurotransmitters. Let’s break these down briefly.
Purines
The purinergic neurotransmitters are adenosine and ATP. You may have heard of adenosine before as it is the molecule that caffeine works to block. These molecules are also involved in metabolism (ATP is the body's primary energy source) and the synthesis of DNA and RNA, though they also have roles in neurotransmission. ATP can be stored in small vesicles alongside other classic neurotransmitters, while adenosine is not stored in vesicles and is released into the synapse by transporter or it is created in the synapse. ATP can be converted into adenosine in the synapse in under one second, making it an important source of extracellular adenosine. These few quirks are enough to earn the title of “atypical”.
Endocannabinoids
Cannabinoids are retroactive messengers synthesized from lipid precursors in the postsynaptic cell in response to strong and extended activation. Once created they travel to the presynaptic cell without a vesicle and act on cannabinoid receptors which slow neurotransmitter release (the same receptors that THC activates). Everything about their function is atypical, from their synthesis to their release and action.
Gasses
Gasses like nitric oxide (NO) and carbon monoxide (CO) are also retroactive messengers. Both are created in the postsynaptic cell, through different mechanisms, and travel to the presynaptic terminal. Since they are small gasses, they can freely pass through any cell membrane with no need for a vesicle. Upon arrival in the presynaptic cell they stimulate production of cGMP, a messenger molecule, that will typically enhance neurotransmitter release through a phosphorylation signaling cascade, making them part of a positive feedback loop in neurotransmission. Similar to endocannabinoids, these are very atypical as they differ from classic neurotransmitters in almost every way, though they have a role in neurotransmission
Conclusion
In the end, there is no “one size fits all” when talking about neurotransmitters. We have molecules ranging from the simplest amino acid to large peptides over two dozen amino acids long. Despite their differences, they all have one thing in common, a role in neurotransmission.